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Clinical and Genetic Characterization of Pituitary Gigantism: an International Collaborative Study in 208 Patients

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Clinical and Genetic Characterization of Pituitary Gigantism: an International Collaborative Study in 208 Patients L Rostomyan, A F Daly et al. Pituitary gigantism 22:5 745–757 Research Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients Liliya Rostomyan*, Adrian F Daly*, Patrick Petrossians, Emil Nachev1, Anurag R Lila2, Anne-Lise Lecoq3,4,5, Beatriz Lecumberri6, Giampaolo Trivellin7, Roberto Salvatori8, Andreas G Moraitis7, Ian Holdaway9, Dianne J Kranenburg - van Klaveren10, Maria Chiara Zatelli11, Nuria Palacios12, Cecile Nozieres13, Margaret Zacharin14, Tapani Ebeling15, Marja Ojaniemi15, Liudmila Rozhinskaya16, Elisa Verrua17, Marie-Lise Jaffrain-Rea18,19, Silvia Filipponi18,19, Daria Gusakova20, Vyacheslav Pronin21, Jerome Bertherat22, Zhanna Belaya16, Irena Ilovayskaya23, Mona Sahnoun-Fathallah24, Caroline Sievers25, Gunter K Stalla25, Emilie Castermans, Jean-Hubert Caberg, Ekaterina Sorkina21, Renata Simona Auriemma26, Sachin Mittal27, Maria Kareva16, Philippe A Lysy28, Philippe Emy29, Ernesto De Menis30, Catherine S Choong31, Giovanna Mantovani17, Vincent Bours, Wouter De Herder10, Thierry Brue24,32, Anne Barlier24,33, Sebastian J C M M Neggers10, Sabina Zacharieva1, Philippe Chanson3,4,5, Nalini Samir Shah2, Constantine A Stratakis7, Luciana A Naves34 and Albert Beckers Departments of Endocrinology and Human Genetics, Centre Hospitalier Universitaire de Lie` ge, University of Lie` ge, Domaine Universitaire du Sart-Tilman, 4000 Lie` ge, Belgium Endocrine-Related Cancer 1Clinical Center of Endocrinology and Gerontology, Medical University, Sofia, Bulgaria 2Department of Endocrinology, King Edward Memorial Hospital, Mumbai, India 3Assistance Publique-Hoˆ pitaux de Paris, Hoˆ pitaux Universitaires Paris-Sud, Service d’Endocrinologie et des Maladies de la Reproduction et Centre de Re´ fe´ rence des Maladies Endocriniennes Rares de la Croissance, Le Kremlin-Biceˆ tre F-94275, France 4UMR S1185, Univ Paris-Sud, F-94276 Le Kremlin-Biceˆ tre, France 5INSERM U1185, Faculte´ de Me´ decine Paris-Sud, F-94276 Le Kremlin-Biceˆ tre, France 6Servicio de Endocrinologı´a y Nutricio´ n, Hospital Universitario La Paz, Madrid, Spain 7Section on Endocrinology and Genetics, Program on Developmental Endocrinology & Genetics & Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA 8Division of Endocrinology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 9Department of Endocrinology, Greenlane Clinical Centre, Auckland, New Zealand 10Section of Endocrinology, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands 11Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Via Savonarola 9, 44121 Ferrara, Italy 12Servicio de Endocrinologı´a, Hospital Universitario Puerta De Hierro, Majadahonda, Madrid, Spain 13Service d’endocrinologie-diabe´ tologie, Centre Hospitalier Lucien Hussel, Monte´ e du Docteur Chapuis BP127, 38 209 Vienne cedex, France 14Murdoch Children’s Research Institute, Royal Children’s Hospital, University of Melbourne, Parkville, Victoria, Australia 15Departments of Internal Medicine and Pediatrics, Oulu University Hospital, University of Oulu, Oulu, Finland 16Departments of Neuroendocrinology and Bone Diseases, and Department of Endocrinology, Endocrinology Research Centre, Moscow, Russia 17Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Unit of Endocrinology and Metabolic Diseases, Department of Clinical Sciences and Community Health, University of Milan, Via F. Sforza, 35, 20122 Milan, Italy 18Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy 19Neuromed IRCCS, Pozzili, Italy http://erc.endocrinology-journals.org q 2015 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-15-0320 Printed in Great Britain Downloaded from Bioscientifica.com at 09/25/2021 08:12:17PM via free access Research L Rostomyan, A F Daly et al. Pituitary gigantism 22:5 746 20Andrology Department, NA Lopatkin Scientific Research Institute of Urology, Moscow, Russia 21Endocrinology Clinic, I.M. Sechenov First Moscow State Medical University, Moscow, Russia 22INSERM U1016, Institut Cochin, Universite´ Paris Descartes, Hoˆ pital Cochin, Service d’Endocrinologie, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France 23Endocrinology Department, Moscow Regional Research & Clinical Institute, Moscow, Russia 24Aix-Marseille Universite´ , CNRS, UMR7286, 13015 Marseille, France 25Department of Endocrinology, Max Planck Institute of Psychiatry, Munich, Germany 26Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, University “Federico II”, Naples, Italy 27Department of Endocrinology, T.N. Medical College & B.Y.L. Nair Hospital, Mumbai, India 28Pediatric Endocrinology Unit, Department of Pediatrics, Clinique Universitaire Saint-Luc, Universite´ Catholique de Louvain, Brussels, Belgium 29Service D’endocrinologie, CHR Orle´ ans, Orle´ ans, France 30Endocrinology, Ospedale Generale Montebelluna, Montebelluna, Italy 31Department of Paediatric Endocrinology, Princess Margaret Hospital for Children and School of Pediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia Correspondence 32Department of Endocrinology, APHM Conception, 13385 Marseille, France should be addressed 33Laboratory of Molecular Biology, APHM Conception, 13385 Marseille, France to A Beckers 34Department of Endocrinology, Faculty of Medicine, University of Brasilia, Brasilia, Brazil Email *(L Rostomyan and A F Daly contributed equally to this work) [email protected] Abstract Despite being a classical growth disorder, pituitary gigantism has not been studied previously Key Words in a standardized way. We performed a retrospective, multicenter, international study to " gigantism characterize a large series of pituitary gigantism patients. We included 208 patients (163 " pituitary adenoma males; 78.4%) with growth hormone excess and a current/previous abnormal growth velocity " somatotropinoma for age or final height O2 S.D. above country normal means. The median onset of rapid growth " growth hormone was 13 years and occurred significantly earlier in females than in males; pituitary adenomas " aryl hydrocarbon receptor were diagnosed earlier in females than males (15.8 vs 21.5 years respectively). Adenomas were interacting protein gene R10 mm (i.e., macroadenomas) in 84%, of which extrasellar extension occurred in 77% and " familial isolated pituitary adenoma (FIPA) invasion in 54%. GH/IGF1 control was achieved in 39% during long-term follow-up. Final " X-linked acrogigantism Endocrine-Related Cancer height was greater in younger onset patients, with larger tumors and higher GH levels. Later (X-LAG) syndrome disease control was associated with a greater difference from mid-parental height (rZ0.23, PZ0.02). AIP mutations occurred in 29%; microduplication at Xq26.3 – X-linked acrogigant- ism (X-LAG) – occurred in two familial isolated pituitary adenoma kindreds and in ten sporadic patients. Tumor size was not different in X-LAG, AIP mutated and genetically negative patient groups. AIP-mutated and X-LAG patients were significantly younger at onset and diagnosis, but disease control was worse in genetically negative cases. Pituitary gigantism patients are characterized by male predominance and large tumors that are difficult to control. Treatment delay increases final height and symptom burden. AIP mutations and X-LAG explain many O cases, but no genetic etiology is seen in 50% of cases. Endocrine-Related Cancer (2015) 22, 745–757 Introduction Interest in the extremes of height stretches back into screening activities in childhood are geared to identifying antiquity, and the occurrence of people with gigantism these cases for early investigation and intervention (Chee- has contributed to popular myths across many cultures. tham & Davies 2014). Overgrowth is less well understood Even with the recognition that many extreme cases of tall and, particularly if unaccompanied by other syndromic stature are disease manifestations, interest in gigantism has features like developmental delay, its diagnosis may be unfortunately remained focused on the visual spectacle, slower. Societal factors may contribute to this, as tall stature even today. Many forms of short stature are known and is seen a less ‘undesirable’ physical feature than short stature http://erc.endocrinology-journals.org q 2015 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-15-0320 Printed in Great Britain Downloaded from Bioscientifica.com at 09/25/2021 08:12:17PM via free access Research L Rostomyan, A F Daly et al. Pituitary gigantism 22:5 747 (Batty et al.2009). However, increased height also carries Belgium, Brazil, Bulgaria, Canada, Denmark, India, Italy, risks in terms of disease (Lee et al.2009), and excessive final Finland, France, Germany, New Zealand, Romania, Russia, adult height carries with it distinct disadvantages, particu- Spain, the Netherlands and the United States. This study larly skeletal and orthopedic problems (Hazebroek-Kamps- was approved by the Ethics Committee of CHU de Lie`ge chreur et al.1994, Silventoinen et al.1999). Surprisingly, the (Belgian clinical trials number: B707201111968). Patients functional and psychological impacts of extreme tall stature were identified at the participating centers and both have yet to be studied
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